Familial cases of pseudohypoaldosteronism type II harboring a novel mutation in the Cullin 3 gene.

Pseudohypoaldosteronism type II (PHA II) is inherited in an autosomal dominant manner and is characterized by hypertension, hyperkalemia, and hyperchloremic metabolic acidosis. The enhancement of with-no-lysine kinase (WNK) functions is correlated to the pathogenesis of the condition. Cullin 3 (CUL3) forms an E3 ubiquitin ligase complex, and it can ubiquitinate WNK. MostCUL3gene mutations are distributed in sites, such as intron 8 splice acceptor, intron 9 splice donor, and putative intron 8 splice branch sites, which are involved in the splicing of exon 9. These mutations result in the deletion of exon 9, which reduces the activity of ubiquitination against WNK and inhibits the degradation of WNK. In this report, we identified a novelCUL3c.1312A>G mutation in familial cases. A mutation prediction software showed that the significance of these mutations was not clear. However, using the Human Splicing Finder 3.1 software, in silico analyses revealed that these mutations induced splicing alterations, which affected the sites of exon 9, altered the balance between predicted exonic splicing enhancers and silencers, and led to the deletions of exon 9. This study presented a novel pathogenic splicing variant to theCUL3mutation and provided a reference for further research about the mechanisms of splicing. Moreover, it showed that not only amino acid substitution caused by nonsynonymous mutations but also splicing motif changes due to base substitutions have important roles in the pathogenesis of PHA II.